Kaposi' sarcoma (KS) is the most common cancer in AIDS patients, and is associated with infection of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). KS is a highly angiogenic vascular neoplasm primarily consisting of proliferating spindle endothelial cells with vast inflammatory infiltration. The long-term goal of our research program is to understand the molecular mechanism of KSHV-induced pathogenesis, providing a scientific basis for developing effective preventive and therapeutic approaches. Recent studies have shown that angiogenesis and inflammation are two central components in KS pathogenesis, and KSHV infection modulates these processes through a paracrine mechanism by inducing pro-angiogenic and inflammatory factors. The objective of this application is to define the mechanisms by which KSHV induces angiogenesis, and identify potential therapeutic targets for KSHV-induced malignancies. Our preliminary studies have shown that KSHV infection of human umbilical vein endothelial cells induces secretion of pro-angiogenic factors and represses secretion of angiogenesis inhibitors. Importantly, we have found that pro-angiogenic factors angiopoietin-2 (Ang-2), interleukin-6 (IL-6), and matrix metalloproteinase-1 (MMP-1) are highly induced by KSHV, and are also highly expressed in KS tumors. Significantly, we have shown that blocking Ang-2 alone with a neutralization antibody abolishes KSHV-induced paracrine-dependent angiogenesis in vivo. We hypothesize that KSHV infection induces angiogenesis through a paracrine mechanism by expressing specific viral gene products to modulate cellular angiogenic pathways, and as a result, targeting these angiogenic pathways can inhibit KSHV- induced tumorigenesis. To test this hypothesis, we will identify KSHV-regulated pro-angiogenic factors and angiogenesis inhibitors essential for KSHV-induced angiogenesis (aim I); determine the cellular pathways that mediate KSHV regulation of Ang-2, IL-6 and MMP-1 in latent infection (aim II); and identify viral genes that regulate the expression of Ang-2 (aim III). Finally, we will test the therapeutic applications of inhibiting KSHV-induced specific angiogenic pathways in tumor animal models (aim IV). The proposed project is innovative because it will use comprehensive multidisciplinary approaches to identify viral and cellular pathways, and pro-angiogenic factors/angiogenesis inhibitors that control KSHV-induced angiogenesis. These studies are significant because it will not only define the mechanism(s) of KSHV-induced angiogenesis but also identify potential therapeutic targets for KSHV-induced malignancies. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma is a common malignancy in AIDS patients in US and worldwide inflicting morbidity and mortality to the society. This project will investigate the mechanism underlining the development of Kaposi's sarcoma, and identify potential targets for the prevention and treatment of this disease.